A chemical chaperone improves muscle function in mice with a RyR1 mutation

Abstract

Mutations in the RYR1 gene cause severe myopathies. Mice with an I4895T mutation in the type 1 ryanodine receptor/Ca2+ release channel (RyR1) display muscle weakness and atrophy, but the underlying mechanisms are unclear. Here we show that the I4895T mutation in RyR1 decreases the amplitude of the sarcoplasmic reticulum (SR) Ca2+ transient, resting cytosolic Ca2+ levels, muscle triadin content and calsequestrin (CSQ) localization to the junctional SR, and increases endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and mitochondrial ROS production. Treatment of mice carrying the I4895T mutation with a chemical chaperone, sodium 4-phenylbutyrate (4PBA), reduces ER stress/UPR and improves muscle function, but does not restore SR Ca2+ transients in I4895T fibres to wild type levels, suggesting that decreased SR Ca2+ release is not the major driver of the myopathy. These findings suggest that 4PBA, an FDA-approved drug, has potential as a therapeutic intervention for RyR1 myopathies that are associated with ER stress.

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

“…Critical for Ca 2+ flow0.710.53058+IVCT[50, 63, 89] 46:33p.Gly2434ArgCS (Bsol)MH/CCD hotspot 2, NTD-Bsol contact (DP4 peptide)0.091.5121125+IVCT ↑, ryanodine binding and ↑ sensitivity to caffeine and 4C m C[13, 18, 49, 58]p.Met4875ValCAC (Pore)MH/CCD hotspot 3, luminal triadin binding, retention of RyR-CSQ proximity and ability for rapid Ca 2+ release0.00.22121None[37, 38, 89]Pore-TMx interface 47:34p.Gly1165GlyCS (SPRY2)Residue close to RyR1-Cav1.1 interaction siten/an/an/an/aNone[64]p.Arg1606HisCS (SPRY3)Probable RyR1-Cav1.1 interaction0.070.12829None[64]SPRY3-RY1&2 interfacep.Glu4167* a CAC (Csol)MH/CCD hotspot 3n/an/an/an/aNone[89] CS CS, CSQ calsequestrin, CAC CAC, MH malignant hyperthermia, CCD central core disease, Bsol bridging solenoid, NTD-B N-terminal domain B, NTD-A N-terminal domain A, SPRY1 SP1a/ryanodine receptor domain 1, Nsol N-terminal solenoid, RY1&2 RYR repeats 1 and 2, SPRY3 SP1a/ryanodine receptor domain 3, Pore chan...…”

Is Gene-Size an Issue for the Diagnosis of Skeletal Muscle Disorders?

“…Similarly, to study the physiopathology of the dominant tibial muscular dystrophy (TMD) and the recessive limb-girdle muscular dystrophy (LGMD2J or LGMD R10 titin-related) due to heterozygosity and homozygosity for the FINmaj mutation, Charton and colleagues generated a mouse model carrying the same mutation [95]. Several RYR1 knock in mouse models have been generated to mimic the equivalent mutations identified in humans [96][97][98][99]. Recently, Laitila and colleagues have generated and characterized a mouse model with compound heterozygous Neb mutations (a missense p.Tyr2303His and a nonsense p.Tyr935*), matching the genotype observed in patients with a nemaline myopathy [100,101].…”

Identification of drug modifiers for RYR1-related myopathy using a multi-species discovery pipeline

“…In addition, two compound heterozygous mouse models of recessive RYR1-RM were with recently generated and characterized (Brennan et al, 2019;Elbaz et al, 2019). These models are complimented by "knock-in" mutants in mice that mirror specific dominant human mutations, including the I4895T mutant (associated with central core disease and referred to as the IT model) (Zvaritch et al, 2007;Zvaritch et al, 2009;Lee et al, 2017), the R163C mutant (associated with malignant hyperthermia) (Yang et al, 2006), and the Y522S mutant (associated with malignant hyperthermia and referred to as the YS mouse) (Chelu et al, 2006;Durham et al, 2008;Lanner et al, 2012;Yarotskyy et al, 2013).…”